Project Summary: Post-traumatic stress disorder (PTSD) is a common neuropsychiatric disorder with an estimated lifetime prevalence of ~8% in the United States of America. Combat-related PTSD, a specific type of PTSD, is found in up to 25% of war veterans who have been in combat and is less responsive to treatment. Over the past two decades, significant progress has been made in understanding the pathophysiology of PTSD, much of which indicates that hypometabolism in the prefrontal cortex plays a major role in the disrupted neural circuitry of mood and cognition. While it is not possible at present to offer a treatment for complete resolution of PTSD symptoms, it is important to develop innovative interventions targeting prefrontal hypometabolism directly in order to improve the cognitive and mood dysfunction inherent in PTSD. Transcranial infrared laser stimulation (TILS) directed at the prefrontal cortex is a non-invasive, non- pharmacologic, portable, convenient, and cost-effective form of photobiomodulation. The mechanism of TILS relies on photoactivation of cytochrome c oxidase (CCO), the terminal enzyme in the mitochondrial respiratory chain that catalyzes the reduction of oxygen for energy metabolism. This photonics-bioenergetics mechanism results in unique functional benefits for neurons by stimulating oxygen metabolism. Our research team has implemented two optical neuroimaging modalities, namely broadband near- infrared spectroscopy (bbNIRS) and functional near-infrared spectroscopy (fNIRS), to directly and quantitatively assess in vivo metabolic/CCO changes during TILS and image the abnormal prefrontal activity in in veterans with PTSD. The use of two innovative optical neuroimaging modalities, along with the promising preliminary results, provides us a solid foundation to further advance studies of PTSD via a clinical trial design to rigorously test TILS as a novel, non-invasive, and non-pharmacologic intervention for PTSD. Specifically, we proposal in a biphasic study among combat-exposed veterans with PTSD in order to 1) elucidate the pathophysiological mechanism of TILS and determine the optimal treatment dosage in the R61 phase, and 2) apply TILS to treat cognitive and mood dysfunction in the R33 phase. We hypothesize that TILS can systematically engage and up-regulate oxygen metabolism and functional activity in the prefrontal cortex, leading to improved cognitive and mood functioning as well as overall symptoms in veterans with PTSD. The outcome of this project will establish whether TILS as a novel, non-invasive, non-pharmacologic and cost-effective therapy can be used to ameliorate cognitive and mood dysfunction, and/or overall symptom severity in combat-related PTSD.